The great promise of nanotechnology is the development of "molecular machines" for a myriad of uses, and especially within biomedicine. Extensive efforts are underway to design and produce such machines from a variety of elements and first principles. We propose to take a "reverse-engineering" approach to this problem by exploiting a molecular machine that has evolved within the microbial world, a bacterial protein injection system called the "molecular syringe." This device has evolved in pathogenic bacteria to precisely deliver protein toxins into human cells, and therefore functions as a "nano-syringe," converting energy into the work of protein injection. We plan to use this injection device to deliver into diseased cells functional versions of eukaryotic proteins that have been mutated or otherwise rendered non-functional in the illness, as well as proteins and peptides that may inhibit the action of malfunctioning proteins. Examples include restoring functional tumor suppressors or pro-apoptotic polypeptides into transformed lines, injecting enzymes mutated in inherited diseases, and adding inhibitors of transcription to achieve a desired shut down in certain genes whose expression leads to pathology. Should these goals be realized, we will have learned to harness an amazing bacterial nano-machine for biomedical applications, providing a new and powerful tool for treating a potentially broad range of diseases. [unreadable] [unreadable] Project Narrative: We propose to adapt a bacterial protein injection system to precisely deliver protein and peptide therapeutics into diseased human cells Examples include restoring functional tumor suppressors or pro-apoptotic polypeptides into transformed lines, injecting enzymes mutated in inherited diseases, and adding inhibitors of transcription to achieve a desired shut down in certain genes whose expression leads to pathology. Should these goals be realized, we will have learned to harness this amazing bacterial nano- machine for biomedical applications, providing a new and powerful tool for treating a potentially broad range of diseases. [unreadable] [unreadable] [unreadable]